WO2023054549A1 - Inducteur de dégradation - Google Patents

Inducteur de dégradation Download PDF

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WO2023054549A1
WO2023054549A1 PCT/JP2022/036353 JP2022036353W WO2023054549A1 WO 2023054549 A1 WO2023054549 A1 WO 2023054549A1 JP 2022036353 W JP2022036353 W JP 2022036353W WO 2023054549 A1 WO2023054549 A1 WO 2023054549A1
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amino
mmol
methylcarbamoyl
reference example
methyl
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淳也 加藤
滋 是永
優 岩倉
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あすか製薬株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)

Definitions

  • the present invention relates to novel compounds or pharmacologically acceptable salts thereof that induce degradation of non-receptor tyrosine kinases. Furthermore, the present invention relates to degradation-inducing agents or pharmaceuticals containing these compounds or pharmacologically acceptable salts thereof. It relates to methods of ameliorating, preventing and/or treating conditions or diseases in need.
  • Non-receptor tyrosine kinases are known to play an important role in the JAK-STAT (Janus kinases-signal transducer and activator of transcription) pathway that transmits signals such as cytokines.
  • JAK Janus Kinase
  • JAKs are tyrosine kinases that bind to cytokine receptors, which are the most upstream in the signal transduction pathway. transcription: STAT). Activated STAT translocates into the nucleus and initiates gene transcription, exerting cytokine functions.
  • the JAK family has four subtypes, JAK1, JAK2, JAK3, and Tyrosine kinase 2 (Tyk2), which are activated by various combinations of JAK-STATs by various cytokines (non-patented Reference 1).
  • JAK1, JAK2, and Tyk2 are expressed in a wide range of cells, whereas JAK3 expression is largely restricted to lymphocytes; JAK2 is known to be responsible for signal transduction of IL-3, 5, granulocyte macrophage colony-stimulating factor (GMCSF), erythropoietin, thrombopoietin, growth hormone, and the like.
  • JAK1 and JAK2 interferon- ⁇ Interferon- ⁇ : IFN- ⁇
  • JAK1 and Tyk2 interferon- ⁇ / ⁇ Interferon- ⁇ / ⁇
  • JAK2 and Tyk2 is known to be involved in IL-12,23 signaling.
  • JAK1, JAK2 and Tyk2 are IL-6, 10, 11, 13, 19, 20, 22, 27, granulocyte colony stimulating factor (Granulocyte Colony Stimulating Factor: GCSF), LIF (leukemia inhibitory factor: Leukemia Inhibitory Factor), and is known to be involved in signal transduction of Oncostatin M (OSM) (Non-Patent Documents 1 and 2).
  • GCSF Granulocyte Colony Stimulating Factor
  • LIF leukemia inhibitory factor: Leukemia Inhibitory Factor
  • OSM Oncostatin M
  • JAK-STAT pathway inhibiting JAK regulates cytokine signal transduction, suppresses the occurrence of adverse events such as symptoms and pathologies caused by various cytokines, autoimmune diseases and inflammatory Studies have been conducted to find ways to help treat diseases, and low-molecular-weight JAK inhibitors have already been approved as therapeutic agents for rheumatoid arthritis and ulcerative colitis. A therapeutic effect on atopic dermatitis and alopecia is also expected by inhibiting JAK1.
  • Non-Patent Document 3 A wide range of autoimmune diseases such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), ankylosing spondylitis, ulcerative colitis, Crohn's disease, type 1 diabetes, and multiple sclerosis have also been demonstrated in humans with inactivated Tyk2 mutants.
  • SLE systemic lupus erythematosus
  • Tyk2 ulcerative colitis
  • Crohn's disease type 1 diabetes
  • multiple sclerosis A wide range of autoimmune diseases such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), ankylosing spondylitis, ulcerative colitis, Crohn's disease, type 1 diabetes, and multiple sclerosis have also been demonstrated in humans with inactivated Tyk2 mutants.
  • Whole-genome association analysis of humans has revealed that it has a preventive effect against immune diseases,
  • Non-Patent Document 1 Non-Patent Document 5
  • JAK inhibitors are low-molecular-weight compounds, they are rapidly excreted from tissues, and there are problems such as the need to administer high doses to increase the local concentration, which is likely to cause side effects.
  • a degradation inducer is a technology that uses the intracellular ubiquitin-proteasome system to degrade a target protein. In recent years, it has attracted attention because it can be applied even when it cannot be suppressed by existing inhibitors (Patent Document 1, Non-Patent Document 6). In addition, since the degradation inducer has a larger molecular weight than inhibitors, which are low-molecular-weight compounds, it has a long local retention time and is easy to maintain local concentration, which can be expected to reduce the dosage and reduce side effects.
  • An object of the present invention is to provide novel compounds or pharmacologically acceptable salts thereof that induce selective degradation of non-receptor tyrosine kinases (especially tyrosine kinases that constitute the JAK family).
  • the object is to provide a non-receptor tyrosine kinase degradation inducer or a medicament containing such a compound or a pharmacologically acceptable salt.
  • Another object of the present invention is to ameliorate, prevent and/or treat conditions or diseases that require regulation such as suppression of activation of cytokine signal transduction pathways, including administration of such degradation-inducing agents or pharmaceuticals.
  • to provide a way to Still another object of the present invention is to provide a screening method for a substance having activity to induce the degradation of non-receptor tyrosine kinases.
  • VHL von Hippel-Lindau
  • E3 ubiquitin ligase a compound obtained by binding a ligand of VHL (von Hippel-Lindau), which is a substrate recognition subunit of E3 ubiquitin ligase, through a linker from a pyridyl or pyridazinyl compound has the JAK family.
  • VHL von Hippel-Lindau
  • the inventors have discovered that selective degradation of the constituent tyrosine kinases can be induced, and have completed the present invention.
  • the gist of the present invention is as follows.
  • R 1 is a hydrogen atom or C 1-3 alkyl optionally substituted with one or more deuterium atoms;
  • R 2 is CONHR 3 (wherein R 3 is C 1-3 alkyl optionally substituted with one or more OH) or triazole optionally substituted with one or more C 1-3 alkyl is;
  • A is pyridyl or pyridazinyl;
  • B is and n is an integer from 0 to 12
  • R 1 is a hydrogen atom, methyl or methyl substituted with 3 deuterium atoms
  • R 2 is CONHCH 3 , CONHCH 2 OH, CONHC 2 H 5 , CONHC 2 H
  • the compound of [1] which is triazole substituted with 4 OH or one methyl group, or a pharmacologically acceptable salt thereof.
  • [6] The degradation inducer of [5], which selectively degrades at least one non-receptor tyrosine kinase selected from the group consisting of JAK1, JAK2, JAK3 and Tyk2.
  • [7] A medicament containing the compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof.
  • IFN ⁇ , IFN ⁇ , IFN ⁇ , IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-11, IL-12, IL-15, IL-19, IL -20, IL-21, IL-22, IL-23, IL-27, G-CSF, LIF and Oncostatin M require suppression of activation of signaling pathway of at least one cytokine
  • the medicament according to [7] which is used for amelioration, prevention and/or treatment of said condition or disease.
  • a method of screening for a substance that induces degradation of non-receptor tyrosine kinase comprising the following steps: (1) coexistence of a candidate substance and a non-receptor tyrosine kinase, and detecting the activity of the candidate substance to induce degradation of the non-receptor tyrosine kinase; and (2) the candidate that degraded the non-receptor tyrosine kinase in (1). selecting a substance as a degradation inducer, provided that the candidate substance has a degradation inducer activity of formula IV If the decomposition-inducing activity is lower than the decomposition-inducing activity of the compound, it is not selected as a decomposition-inducing substance.
  • the compound represented by the above formula I or a pharmacologically acceptable salt thereof provided by the present invention has a selective degradation-inducing activity of non-receptor tyrosine kinases, particularly JAK, Drugs for the prevention or treatment of, for example, autoimmune diseases, inflammatory diseases, COVID-19 infections, cancer, atopic dermatitis, alopecia, etc., since they can regulate the activation of signal transduction pathways, etc. It is also useful as a research reagent.
  • FIG. 2 shows the results of detection of JAK1, JAK2, JAK3, Tyk2 and GAPDH protein levels in Jurkat cells after treatment with each test compound for 6 hours by chemiluminescence Western blotting. 1. It is the graph which quantified the detection result of the chemiluminescence western blotting shown in FIG.
  • the present invention relates to a compound represented by Formula I below, or a pharmacologically acceptable salt thereof.
  • R 1 is a hydrogen atom or C 1-3 alkyl optionally substituted with one or more deuterium atoms.
  • R 1 is preferably a hydrogen atom or methyl or ethyl optionally substituted with 3 deuterium atoms, more preferably a hydrogen atom, methyl or methyl substituted with 3 deuterium atoms or ethyl, and even more preferably a hydrogen atom, methyl or methyl substituted with 3 deuterium atoms.
  • R 2 is CONHR 3 (wherein R 3 is C 1-3 alkyl optionally substituted with one or more OH) or triazole optionally substituted with one or more C 1-3 alkyl is.
  • R 2 is preferably CONHCH 3 , CONHCH 2 OH, CONHC 2 H 5 , CONHC 2 H 4 OH or triazole optionally substituted by one or more methyl or ethyl, more preferably CONHCH 3 , CONHC 2 H 4 OH or triazole optionally substituted with one methyl.
  • A is pyridyl or pyridazinyl.
  • R 1 is a hydrogen atom or C 1-3 alkyl, A is preferably pyridyl.
  • R 1 is C 1-3 alkyl substituted with one or more deuterium atoms, A is preferably pyridazinyl.
  • B is is.
  • R 1 is a hydrogen atom or C 1-3 alkyl
  • B is preferably is.
  • R 1 is C 1-3 alkyl substituted with one or more deuterium atoms, B is preferably is.
  • n is an integer from 0 to 12.
  • n is preferably 1 or more, and may be 2 or more, 3 or more, or 4 or more, but is preferably 11 or less, and may be 10 or less, 9 or less, or 8 or less.
  • n is, for example, 0 to 12, 1 to 12, 2 to 12, 3 to 12, 4 to 12, 5 to 12, 6 to 12, 0 to 11, 1 to 11, 2 to 11, 3 to 11, 4 ⁇ 11, 5 ⁇ 11, 6 ⁇ 11, 0 ⁇ 10, 1 ⁇ 10, 2 ⁇ 10, 3 ⁇ 10, 4 ⁇ 10, 5 ⁇ 10, 6 ⁇ 10, 0 ⁇ 9, 1 ⁇ 9, 2 ⁇ 9 , 3 to 9, 4 to 9, 5 to 9, 6 to 9, 0 to 8, 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8 good.
  • n is preferably in the range of 3 to 9, 4 to 9, 5 to 9, 6 to 9, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 5 to 8, 6 to 9, A range of 6 to 8 is more preferred.
  • the configuration of the two asymmetric carbons on pyrrolidyl may be 2S,4R configuration or 2S,4S configuration.
  • the preferred configuration of the two asymmetric carbons on pyrrolidyl is the 2S,4R configuration.
  • the preferred configuration of the two asymmetric carbons on pyrrolidyl is the 2S,4S configuration.
  • C 1-3 alkyl means a linear or branched alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, isopropyl group, etc.).
  • the term "pharmacologically acceptable salt” is not particularly limited as long as it is a pharmaceutically acceptable salt, and can be appropriately selected depending on the purpose.
  • salts with inorganic acids such as hydrochloric acid and sulfuric acid
  • salts with organic acids such as maleic acid and tartaric acid
  • salts with alkali metals such as sodium and potassium
  • salts with alkaline earth metals such as calcium and magnesium
  • diethylamine and salts with organic bases such as diethanolamine.
  • the compound of Formula I provided by the present invention is represented by Formula II (In the formula, R 1 is a hydrogen atom, methyl or ethyl; R 2 is CONHR 3 (wherein R 3 is C 1-3 alkyl optionally substituted with one or more OH) or triazole optionally substituted with one or more methyl or ethyl ; and n is an integer from 1 to 12) It is a compound represented by or a pharmacologically acceptable salt thereof.
  • R 1 is preferably hydrogen or methyl
  • R 2 is preferably CONHR 3 , wherein R 3 is methyl or ethyl optionally substituted with one or more OH ) or triazole optionally substituted with one or more methyl or ethyl
  • n is 1-12, 2-12, 3-12, 4-12, 5-12, 6-12, 1-11, 2-11, 3-11, 4-11, 5-11, 6-11, 1-10, 2-10, 3-10, 4-10, 5-10, 6-10, 1-9, 2- It is preferably in the range of 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 ⁇ 9, 4-9, 5-9, 6-9, 3-8, 4-8, 5-8, 6-8 is more preferable, 5-8, 6-9, 6-8 is more preferably in the range of
  • the compound represented by Formula I, or a pharmaceutically acceptable salt thereof is represented by Formula III (In the formula, R 1 is methyl substituted with 3 deuterium atoms; R 2 is triazole optionally substituted with one or more methyl or ethyl; B is ; and n is an integer from 1 to 12) It is a compound represented by or a pharmacologically acceptable salt thereof.
  • R 2 is preferably triazole optionally substituted with 1 methyl or ethyl, more preferably triazole substituted with 1 methyl or ethyl
  • n is 1 ⁇ 12, 2 ⁇ 12, 3 ⁇ 12, 4 ⁇ 12, 5 ⁇ 12, 6 ⁇ 12, 1 ⁇ 11, 2 ⁇ 11, 3 ⁇ 11, 4 ⁇ 11, 5 ⁇ 11, 6 ⁇ 11, 1 ⁇ 10 , 2-10, 3-10, 4-10, 5-10, 6-10, 1-9, 2-9, 3-9, 4-9, 5-9, 6-9, 1-8, 2 8, 3-8, 4-8, 5-8, 6-8, n is 3-9, 4-9, 5-9, 6-9, 3-8, 4 It is more preferably in the range of ⁇ 8, 5-8, 6-8, even more preferably in the range of 5-8, 6-9, 6-8.
  • the compounds represented by Formula I, II or III or their pharmacologically acceptable salts may be collectively referred to as "the compounds of the present invention”.
  • a degradation-inducing agent for non-receptor tyrosine kinases containing the compound of the present invention is provided.
  • the non-receptor tyrosine kinase degradation inducer containing the compound of the present invention preferably selectively degrades at least one non-receptor tyrosine kinase selected from the group consisting of JAK1, JAK2, JAK3 and Tyk2.
  • the degradation inducer of non-receptor tyrosine kinases containing the compounds of the present invention is a selective degradation inducer of JAK1 and Tyk2.
  • the degradation inducer of non-receptor tyrosine kinases containing the compounds of the present invention is a selective degradation inducer of Tyk2.
  • a medicament containing the compound of the present invention is provided.
  • the compounds of the present invention can regulate, such as suppression of activation of cytokine signaling pathways mediated by the non-receptor tyrosine kinases.
  • JAK1 and Tyk2 are IFN ⁇ , IFN ⁇ , IFN ⁇ , IL-6, IL-10, IL-11, IL-12, IL-19, IL-20, IL-22, IL-23, LIF, Oncostatin M It is thought that these cytokines are involved in the prevention and treatment of autoimmune diseases, inflammatory diseases, COVID-19 infections, cancer, atopic dermatitis, alopecia, etc. .
  • autoimmune diseases such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, ulcerative colitis, Crohn's disease, type 1 diabetes, multiple sclerosis, and T-cell acute lymphocytic leukemia , anaplastic large cell lymphoma, and malignant nerve sheath tumor.
  • cancer means all malignant neoplasms, whether epithelial or non-epithelial.
  • the subject of administration of the pharmaceutical of the present invention is not limited as long as it is an animal, but preferably mammals, more preferably humans.
  • the compound of the present invention may be administered as it is, or it may be formulated and administered by a conventional method in combination with a pharmaceutical carrier commonly used by those skilled in the art.
  • Pharmaceutical carriers include, for example, excipients, binders, fillers, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, flavoring agents, perfumes, coating agents, diluents, and coloring agents. etc., can be appropriately selected depending on the purpose such as the form of the drug and the provision of sustained release properties.
  • the dosage form of the medicament of the present invention is not particularly limited, and can be appropriately selected as needed.
  • Oral drugs such as oral tablets, oral sprays, injections, ointments, inhalants, eye drops, ophthalmic ointments, nose drops, suppositories, external solid formulations, external liquid formulations, sprays, creams, Parenteral agents such as gels and patches can be mentioned, but are not limited to these.
  • the administration route of the medicament of the present invention is appropriately selected in consideration of the type and degree of the condition or disease to be improved, prevented and/or treated, the subject's age, gender difference, drug sensitivity difference, and the like.
  • Examples thereof include oral administration, intravenous administration, nasal administration, transdermal administration, transmucosal administration, intra-articular administration, transpulmonary/bronchial administration, transrectal administration, and transocular administration.
  • the compounds of the invention can also be used as research reagents.
  • the compounds of the present invention can be used as positive controls for screening substances having non-receptor tyrosine kinase degradation-inducing activity.
  • the compounds of the present invention can be used as negative controls for screening substances having non-receptor tyrosine kinase degradation-inducing activity.
  • the compounds of the present invention can be produced using suitable intermediates, known compounds and reagents, for example, by the methods shown in the schemes below.
  • compound (11) corresponds to a compound of formula I, wherein R 1 , R 2 , A and B have the same definitions given for formula I above.
  • Step 3 Compound (6) can be obtained by subjecting compound (5) to alkaline hydrolysis.
  • Step 4 Compound (8) can be obtained by amidation reaction of compound (6) and commercially available reagent (7).
  • Process 5 Compound (9) can be obtained by subjecting compound (8) to alkaline hydrolysis.
  • the target compound (11) can be obtained by subjecting compound (9) to an amidation reaction with compound (10) obtained according to a known method (WO2016/118666).
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • Methyl 12-(6-((4-(2-methoxy-3-(methylcarbamoyl)phenyl)amino)-5-(methylcarbamoyl)pyridin-2-yl)amino)nicotinamide)dodecanoate (Reference Example 10) ( 146 mg, 0.22 mmol), and the same procedure as in Reference Example 11 was performed to obtain the title compound (94.0 mg, 0.15 mmol, yield 66%).
  • Example 1 6-((5-((4-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)) )carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-oxobutyryl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy- 3-(methylcarbamoyl)phenyl)amino)-N-methylnicotinamide
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • Example 2 6-((5-((6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)) )carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy -3-(methylcarbamoyl)phenyl)amino)-N-methylnicotinamide
  • Example 3 6-((5-((8-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)) )carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-8-oxooctyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy -3-(methylcarbamoyl)phenyl)amino)-N-methylnicotinamide
  • Example 4 6-((5-((9-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)) )carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-9-oxononyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy- 3-(methylcarbamoyl)phenyl)amino)-N-methylnicotinamide
  • Example 5 6-((5-((10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)) )carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy- 3-(methylcarbamoyl)phenyl)amino)-N-methylnicotinamide
  • Example 6 6-((5-((11-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)) )carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy- 3-(methylcarbamoyl)phenyl)amino)-N-methylnicotinamide
  • Example 7 6-((5-((12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)) )carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy -3-(methylcarbamoyl)phenyl)amino)-N-methylnicotinamide
  • Example 8 The synthesis scheme of Example 8 is shown below.
  • Example 8 6-((5-((10-(((S)-1-((2S,4S)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)) )carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy- 3-(methylcarbamoyl)phenyl)amino)-N-methylnicotinamide
  • Example 9 The synthesis scheme of Example 9 is shown below.
  • Example 9 6-((5-carbamoyl-4-((2-methoxy-3-(methylcarbamoyl)phenyl)amino)pyridin-2-yl)amino)-N-(10-(((S)- 1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutane- 2-yl)amino)-10-oxodecyl)nicotinamide
  • Example 10 The synthesis scheme of Example 10 is shown below.
  • Example 10 6-((5-((10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)) )carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl)carbamoyl)pyridin-2-yl)amino)-4-((2-methoxy- 3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylnicotinamide
  • Example 11 The synthesis scheme of Example 11 is shown below.
  • Example 11 6-((5-((10-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)) )carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl)carbamoyl)pyridin-2-yl)amino)-4-((3-(( 2-Hydroxyethyl)carbamoyl)-2-methoxyphenyl)amino)-N-methylnicotinamide
  • JAK family proteins The degradation-inducing effect of the compounds of the present invention on JAK family proteins was evaluated in vitro using Jurkat cells, which are cell lines derived from human leukemia T cells.
  • JAK1, JAK2, JAK3 and Tyk2-positive Jurkat cells were seeded at a density of 1 ⁇ 10 5 cells/mL in a dish with a diameter of 10 cm. Wako Pure Chemical Industries: catalog number: 189-02025) and cultured at 37°C in 5% CO 2 for 3 days. Thereafter, each test compound (compounds of Examples 1 to 11 and Comparative Examples 1 and 2) was added to the dish to a final concentration of 1 ⁇ mol/L, and the cells were cultured in the presence of each test compound for 6 hours.
  • the cell culture medium was collected in a 15 mL centrifuge tube (1000 rpm (240 x g), room temperature, 5 min), washed with PBS (1000 rpm (240 x g), room temperature, 5 min), and then 1.5 Cells were collected in mL tubes (3000 rpm (860 ⁇ g), 4° C., 5 min). Cells were then lysed using RIPA buffer (25 mmol/L Tris-HCl (pH 7.4), 25 mmol/L NaCl, 0.5 mmol/L EGTA (pH 8.0), 0.1% SDS, 1% protease inhibitor).
  • RIPA buffer 25 mmol/L Tris-HCl (pH 7.4), 25 mmol/L NaCl, 0.5 mmol/L EGTA (pH 8.0), 0.1% SDS, 1% protease inhibitor).
  • FIG. 1 shows the detection results.
  • Table 5 shows the primary and secondary antibodies used for detection.
  • the luminescence levels of JAK1, JAK2, JAK3 and Tyk2 detected by chemiluminescence western blotting were quantified using the analysis software attached to the fully automated western blotting device (Compass software for Simple Western (version 4.0.0)).
  • the numerical value (target protein amount/GAPDH protein amount) corrected by the protein amount of GAPDH, which is an internal standard protein, was calculated and compared between test compounds with dimethyl sulfoxide (DMSO) as 100%. The results are shown in FIG. 2 and Table 6.
  • the compounds of the present invention have non-receptor tyrosine kinases, in particular, JAK selective degradation-inducing activity, and can regulate the activation of cytokine signal transduction pathways carried by JAKs, such as by suppressing them. It can be used as a drug for prevention or treatment of sexually transmitted diseases, COVID-19 infection, cancer, atopic dermatitis, alopecia, etc., and can also be used as a research reagent.

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Abstract

La présente invention concerne un nouveau composé qui induit une dégradation sélective d'une tyrosine kinase non-réceptrice (et en particulier une tyrosine kinase qui constitue la famille JAK), ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne un composé représenté par la formule I [formule 1] (dans la formule, R1 représente un atome d'hydrogène ou un groupe alkyle en C1-3 qui peut être substitué par un ou plusieurs atomes de deutérium ; R2 représente CONHR3 (dans la formule, R3 représente un groupe alkyle en C1-3 qui peut être substitué par un ou plusieurs groupes OH) ou un groupe triazole qui peut être substitué par un ou plusieurs groupes alkyle en C1-3 ; A est un groupe pyridyle ou un groupe pyridazinyle ; B est représenté par [formule 2] ; et n est un nombre entier compris entre 0 et12), ou un sel pharmaceutiquement acceptable de celui-ci.
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WO2016118666A1 (fr) 2015-01-20 2016-07-28 Arvinas, Inc. Composés et procédés pour la dégradation ciblée du récepteur des androgènes
WO2020009176A1 (fr) 2018-07-04 2020-01-09 田辺三菱製薬株式会社 Composé amide ayant une action induisant une protéolyse bet et utilisation médicinale de celui-ci
WO2020069117A1 (fr) * 2018-09-27 2020-04-02 Dana-Farber Cancer Institute, Inc. Dégradation de fak ou fak et alk par conjugaison d'inhibiteurs de fak et d'alk avec des ligands de ligase e3 et procédés d'utilisation
WO2020086616A1 (fr) * 2018-10-22 2020-04-30 Fronthera U.S. Pharmaceuticals Llc Inhibiteurs de tyk2 et leurs utilisations
WO2020200291A1 (fr) * 2019-04-02 2020-10-08 Cullgen (Shanghai) , Inc. Composés et méthodes de traitement de cancers
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WO2016118666A1 (fr) 2015-01-20 2016-07-28 Arvinas, Inc. Composés et procédés pour la dégradation ciblée du récepteur des androgènes
WO2020009176A1 (fr) 2018-07-04 2020-01-09 田辺三菱製薬株式会社 Composé amide ayant une action induisant une protéolyse bet et utilisation médicinale de celui-ci
WO2020069117A1 (fr) * 2018-09-27 2020-04-02 Dana-Farber Cancer Institute, Inc. Dégradation de fak ou fak et alk par conjugaison d'inhibiteurs de fak et d'alk avec des ligands de ligase e3 et procédés d'utilisation
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